3-thioketals of pregnadiene and method of preparation thereof



United States Patent 3,192,202 3-THIOKETALS 0F PREGNADHENE AND METHOD OF PREPARATION THEREOF George Karrnas, Bound Brook, and Irving Scheer, Somerville, N.J., assignors to Ortho Pharmaceutical Corporation, a corporation of New Jersey No Drawing. Filed Mar. 12, 1964, Ser. No. 351,515

. 18 Claims. (Cl. zen-239:5

This invention relates to novel methods of preparing 6a-methyl-4-pregnen-17a-ol-20-one and esters thereof and a to novel intermediates prepared by such methods.

r6et-methyl-4-pregnen-tl7a-ol 20-one and its esters have been found to be potent progestational agents and are the subject of United States Serial No. 125,995, filed July 24, 1961. It is an object of the present invention to provide novel methods of preparing 6u-methyl-4-pregnen-l7a-ol-20-one and esters thereof.

It is also an object of the present invention to provide novel thioketal com-pounds.

Other objects will be apparent from the detailed description of the invention hereinafter provided.

The reaction sequence of the present invention is as follows:

"ice

lfi CO1.

In the foregoing reaction sequence, R is hydrogen or methyl, R is ethylene or propylene, R" is the acyl residue of an organic carboxylic acid and X is chlorine, bromine or iodine.

The novel compound 6a-methyl16u,17a-epoxyprogesterone-3aalkylenethioke-tal (IV) can be prepared by alternate routes starting with 6a-methyl-l6-pregnene-3,ZO-dione (I). Compound I may either be epox-idized to form 6a-methyl-16a,17a-epoxyprogesterone (II) with subsequent thioketalization to form Compound IV, or Compound I may be selectively thioketalized to form the novel compound 6or-methyll6-pregnene-3,20-dione 3- alkylenethioketal (III) with subsequent epoxidation to form Compound IV.

Th-ioketalization is carried out with an alkyl dithiol,

such as ethanedithiol, 1,2-propanedithiol or 1,3-propanedithiol, in the presence of a catalyst. The preferred catalyst is pyridine hydrochloride.

Epoxidization is carried out with an alkaline solution of hydrogen peroxide.

The 16a,17u-epoxy group is hydrohalogenated to form the novel 6a-methyl-l6,8-halo-4pregnen-l7a-ol-3, 20-dione 3-alkyl-enethioketa1 (V). Hydrohalogenation may be carried out through the use of hydrogen bromide, hydrogen chloride or hydrogen iodide in an aqueous or non-aqueous media. Upon simultaneous desulfurization and 'de'halogenat-ion with Raney nickel L-II1flly1-4-Pf6gn@l1-17ot-Ol- 20-one (V1) is formed. Compound VI is then esterified to form the ester (VII).

The following examples are intended to illustrate, but not to limit, the scope of the present invention.

EXAMPLE I 6 ot-methyl-4,1 6-pregnadi ens-3,2 O-dione 3-ethylenethioketal A solution of 3.0 grams of 6rz-methyl-l 6-dehydroprogesterone in 15 ml. of tetrahydrofuran is diluted with 25 ml. .of methanol and stirred at 25 C. While 5.0 grams of pyridine hydrochloride is added. After dissolution of the latter, 1.3 ml. of ethanedithiol is added over a period of five minutes and the clear reaction mixture is maintained at 25 C. for two hours and then at 40 C. for ten minutes. One hundred ml. of water is now added and the organic solvents are removed by concentration under reduced pressure. The reaction product is a viscous oil. After isolation by extraction with other a portion of the thioketal may be crystallized directly from ether, but it is preferably purified by development on a column of neu tral alumina and elut-ion with 20% benzene-in-hexane. The crystalline eluates thus obtained are combined and recrystallized from a small amount of ethyl ether to afford 60c methyl 4,16 pregnadiene 3,20 dione 3 ethyl- 3 enethioketal as fine white prisms which melt at 169- 170 C..

Anlalysz'sw- Calcd. for C H OS C, 71.64; H, 8.51. Found: C, 71.64; H, 8.62.

Max.: 600,628, 7.18.08, 9.60, 10.20, 11.00, 11.40, 12.00g.

EXAMPLE II 4,16-pregnadiene-3,ZO-dione 3-ethylenethioketal A solution of 3.0 g. of 16-dehydroprogesterone and 2.0 g. of pyridine hydrochloride in 50 ml. of methanol is stirred vigorously at C. while 1.0 ml. of ethanedithiol is added over a period of'one minute. The clear solution is held at 25 C. for two hours and then at C. for ten minutes and then it is diluted with 200 ml. of water and concentrated under vacuum to remove methanol. The tacky insoluble product is extracted with two 75 ml. portions of ethyl ether, and after evaporation of the ether solution the residue is developedonto a chromatographic column of neutral alumina. Elution with benzene-hexane affords a crystalline residue which is recrystallized from EXAMPLE III 4,16-pregnadiene-3,20-di0-ne 3-trimethylenethi0ketal A solution of 6.0 g. of 16-dehydropr0gesterone and 6.0 g. of pyridine hydrochloride in 200 ml. of methanol. is stirred vigorously while 2.5 ml. of 1,3-propanedithiol is added. The clear solution is held at 25 C. for one hour andthen at C. for twenty minutes and then it is diluted with 200 ml. of water and concentrated under vacuum to remove methanol. The tacky insoluble product is extracted with two 100 ml. portions of ethyl ether and after evaporation of the ether solution the residue is developed onto a chromatographic column of neutral alumina. Elution with ether-hexane affords a crystalline residue which is recrystallized from ethyl acetate to yield 1.4 g. of 4,16pregnadiene-3,20-dione 3-trimethylenethioketal as white prisms which melt at 186188 C.

Analysis.Calcd. for C H OS C, 71.64; H, 8.51. Found: C, 70.11; H, 8.38.

M Max.: 6.00, 6.29, 8.10, 11.61, 12.19, 12.83

In like manner 6a-methyl-4,16-pregnadiene-3,20-dione 3-trimethylenethioketal is prepared starting with methyl-16-dehydroprogesterone.

EXAMPLE IV 6 a-methy l-] 6 0a,] 704-@ pox-y progesterone A solution of 2 g. of 6a-methyl-16-pregnener3,20-dione in 300 ml. of methanol is cooled to 5 C. and stirred while 4.8 ml. of 2.65 N. aqueous sodium hydroxide is 4 EXAMPLE v 6a-methyl-16a,17a-ep0xyprogesterone S-ethylenethioketal PROCEDURE A A solution of 0.6 g. of 6u-methyl-16-pregnene-3,20- dione 3-ethylenethioketa1 in 15 ml. of tetrahydrofuran plus 6 ml. of methanol plus 3 ml. of water is stirred at 5 C. while a solution of 0.25 g. of sodium hydroxide in 2 ml. of water and 3 ml. of methanol is added, followed immediately by 2.4 ml. of aqueous 30% hydrogen peroxide. This mixture is stirred at 5 C. for fourteen hours and is then diluted with 70 ml. of water, precipitating the crystalline epoxide which is filtered off and dried in air. Recrystallization of the crude epoxide from ethyl ether affords 6oc-methyl-16a,17ot-epoxyprogesterone 3ethylene thioketal as white prisms which melt at 143-144 C.

AmZlysis.Calcd. for C H 4O S C, 68.93; H, 8.18. Found: C, 68.59; H, 8.32. I

M Max.: 5.86, 7.22, 9.18, 10.92, 11.70,u.

PROCEDURE '3 To a solution=of 0.4 vg. of 6a-methyl-16a,17u-epoxyprogesterone in 6 ml. of methanol is added 0.5 ml. of ethanedithiol and 0.5 g. of pyridine hydrochloride and this'mixture is stirred at 25 C. for ninety minutes and then at 0C. for thirty minutes. The crystalline 60cmethyl-16oc,17ot epoxyprogesterone 3 ethylenethioketal which has formed is filtered off, washed with cold methanol and dried in air. As thus obtained, thismaterial melts at -142 C. and has an infrared spectrum identical with that described in Procedure A.

EXAMPLE VI 1 6 0c,] 7 u-epoxy progesterone S-ethylenethioketal PROCEDURE A A solution of 2.0 g. of 16-dehydroprogesterone 3- ethylenethioketal in 50 ml. of tetrahydrofuran is diluted with 15 ml. of methanol plus 8 ml. of water and then is stirred at 0-5 C. while a solution of 0.75 g. of sodium hydroxide in 6.5 ml. of water is added and followed immediately by the addition of 8 m1. of 30% aqueous hydrogen peroxide. This reaction mixture is stirred at 5 C. for eighteen hours and then it is slowly diluted with 100 ml. of water. The white crystals of epoxide are filtered oif and are recrystallized from ethyl acetate to af ford 1.9 g. of 16a,17a-epoxyprogesterone 3-ethylenethioketal as fine white prisms which melt at -187 C.

PROCEDURE B A mixture of 2 g. of 16a,17a-epoxyprogesterone, 2 g.

of pyridine hydrochloride and 2 ml. of ethanedithiol in a EXAMPLE VII t 1 6a,]7a-ep0xypr0gester0ne 3-trimethylenethio ketal PROCEDURE A A solution of 1.2 g. of 16-dehydroprogesterone 3-trimethylenethioketal in 32 ml. of tetrahydrofuran is diluted with 15 ml. of methanol plus 7.5 ml. of water and then is stirred at 0 5 C. while a solution of 0.75 g. of sodium hydroxide in 3 ml. of water is added and followed immediately by the addition of 3.75 ml. of 30% aqueous hydrogen peroxide.- This reaction mixture is stirred at 5 C. for eighteen hours and then it is slowly diluted with 100 ml. of water. The crystalline epoxide is filtered oh and dried in air, and then it is recrystallized from ethyl acetate to afford 1.0 g. of 16a,17a-epoxyprogesterone 3-trimethylenethioketal as white prisms which melt at 194-196 C.

PROCEDURE B A mixture of 5.0 g. of 16a,17a-epoxyprogesterone, 5.0 g. of pyridine hydrochloride and 5 ml. of 1,3-propanedithiol in 70 ml. of methanol is stirred at 25 C. for two hours and then it is stored at C. for twenty hours. The crude thioketal is filtered off, washed with cold methanol, dried in air, and recrystallized from ethyl acetate to afford 2.0 g. of 16a,l7a-epoxyprogesterone 3-trimethylenethioketal as White prisms which melt at 194-196", and are identical with the material prepared by Procedure A.

Analysis-Calm. for (3 1-1 0 8 C, 68.93; H, 8.18. Found: C, 69.21; H, 8.42.

M Max.: 5.85, 10.31, 11.08, 11.57, 12.90, 1442 EXAMPLE VIII 6 oc-m ethyl-J 6 ,8-br0m0-4-pregnem1 7a-0l-3,20-di0ne 3-ethylenethioketal A suspension of 0.8 g. of 6a-methyl-16a,17cr-epoxyprogesterone 3-ethylenethioketal in 8 ml. of glacial acetic acid is stirred at 18 C. while 2 ml. of 15% hydrogen bromide-in-glacial acetic acid is added. This reaction mixture is maintained at 18-20 C. for fifteen minutes and at 25 C. for thirty minutes and then it is diluted with 35 ml. of water. The crystalline white bromohydrin which is thus precipitated is filtered off, washed well with water, and is dried in air. As thus obtained, it is suitable for reduction with Raney nickel.

For characterization, 6ot-methyl-16fi-bromo-4-pregnen- 17u-ol-3,20-dione 3-ethylenethioketal may be obtained as white prisms which melt with decomposition at 171-l74 C. by recrystallization from ether-methanol.

AHGZYSiSr-CFllCd. for. C24H3502S2BI': C, H, 7.06. Found: C, 57.74; H, 7.29.

M Max.: 2.90, 5.82, 7.37, 10.10, 11.47, 12.20, 13.80 1.

EXAMPLE 1X 1 6B-chl0ro-4-pregnen-1 7a-0l-3,20-di0 ne 3-ethylenethi0ketal A mixture of 1.0 g. of 16a,l7u-epoxyprogesterone 3-ethylenethioketal and 0.6 ml. of 35% aqueous hydrogen chloride in ml. of acetone is boiled under reflux for two hours and then it is diluted with 40 ml. of water and stored at 0 C. until the insoluble chlorohydrin is crystalline enough to be isolated by filtration. The material thus obtained weighs 1.08 g. and is suitable for reduction with Raney nickel.

For characterization, 16fl,chloro-4-pregnen-17a-ol-3,20- dione 3-ethylenethioketal is obtained as white prisms which melt at 191193 by recrystallization from methylene chloride-methanol.

Analysz's.Calcd. for C H O S Cl: C, 62.63; H, 7.54. Found: C, 62.30; H, 7.58.

Mt MaX.: 2.91, 5.83, 10.17, 11.71, 12.04, 12.90, 13.70,

EXAMPLE X 16,8-br0m0-4-pregnen-17a-0l-3,20-di0ne 3-ethylenethioketal A. mixture of 1.9 g. of 16a,17or-epoxyprogesterone 3-ethylenethioketal and 36 ml. of acetic acid is stirred at 18 C. while 4.8 ml. of 15% hydrogen bromide-in-glacial acetic acid is added over a period of five minutes. This reaction mixture is maintained at 18-20 C. for one hour andthen it is slowly diluted with 500 ml. of Water. The insoluble crystalline White bromohydrin is filtered oif, washed well with water and dried in air to afford 2.25 g. which melts at 192195 C. (with decomposition). As

6 thus obtained, it is' suitable for reduction with Raney nickel.

For characterization, 16fi-bromo-4-pregnen-17u-ol-3,20- dione 3-ethylenethioketal is recrystallized from methylene chloride-ethyl ether to white prisms which melt at 196- 198 C.

Analysis.Calcd. for C H O S Br: C, 56.97; H, 6.85. Found: C, 56.78; H, 7.01.

M Max: 2.90, 5.81, 10.17, 11.70, 12.79, 13.20, 13.81, 14.70/J..

EXAMPLE XI 16fl-i0d0-4-pregnen-1 7oc-0l-3,20-dione 3-ethylenethiokeial A mixture of 1.0 g. of 16a,17a-epoxyprogesterone 3-ethylenethioketal and 1.4 ml. of 60% aqueous hydrogen iodide in 20 ml. of acetone is boiled underrefiux 'for fifteen minutes and then it is diluted with a solution of EXAMPLE XII 16fl-br0m0-4-pregnem1 7a-0l-3,20-di0ne S-trimethylenethioketal A mixture of 1.0 g. of 16a,l7a-epoxyprogesterone 3-trimethylenethioketal, 10 ml. of acetic acid, and 1.0 ml. of 30% hydrogen bromide-in-glacial acetic acid is stirred at 18 C. for fifteen minutes and then at 25 C. for thirty minutes, and then it is slowly diluted with 30 ml. of water. The insoluble crystalline white bromohydrin is filtered off, washed well with water and dried in air. The 1.25 g. of crude product thus obtained is suitable for reduction with Raney nickel.

For characterization, 16B-bromo-4-pregnen-17a-ol-3,20- dione 3-trimethylenethioketal is recrystallized from ethyl ether to white prisms which melt at -177".

Arralysis.Calcd. for C H O S Br: C, 57.70; H, 7.06. Found: C, 57.89; H, 7.21.

M Max.: 2.92, 5.81, 9.53, 10.18, 11.70, 12.26, 12.89, 13.23, 13.85,u.

EXAMPLE XIII 6oc-methyl-4-pregnen-17a-0l-20-0ne One teaspoon (approximately 11 g.) of Raney nickel catalyst, after neutralization with acetic acid and Washing with Water and methanol, is suspended in 200 ml. of methanol. This mixture is stirred while a solution of 6a-methyl-16fl-bromo-4-pregnen-17oc-ol-3,20-dione 3-ethylenethioketal (from 0.8 g. of 6a-methyl-l6a,17-a-epoxyprogesterone 3-ethylenethioketal) in 50 ml. of tetrahydrofuran is added and the reaction mixture is stirred at 25 C. for two hours. After removal of the catalyst by filtration, the methanolic filtrate is concentrated under reduced pressure and the residue is dissolved in methylene chloride. This solution is washed with water, dried with magnesium sulfate, and concentrated under reduced pressure to a slightly tacky crystalline residue whose infrared spectrum is in excellent accord with that of 6u-methyl-4-pregnen- 17a-ol-20-one prepared by other methods. If desired, it may be recrystallized from methanol to afford white prisms which melt at 182-186 C.

M Max.: 2.88, 5.88, 7.40, 9.10, 12.38, 14.83 0.

7 EXAMPLE XIV 4-pregnen-1 7a-0l-20-0ne Two teaspoons (approximately 22 g.) of Raney nickel catalyst, after neutralization with acetic acid and washing with water and methanol; is suspended in 200 ml. of methanol. This mixture is stirred while a solution prepared from the crude 16B-bromo-4-pregnen-17a-ol-3,20- dione 3-ethylenethi'oketal (from 1.0 g. of the corresponding 16a,17-u-epoxide) in 20 ml. of tetrahydrofuran is added. The reaction mixture is stirred at C. for one and one-half hours and then it is filtered to remove the catalyst. The methanolic filtrate is evaporated to dryness and the solidresidue is dissolved in ethyl ether which is washed With Water and then evaporated to a crystalline residue which is recrystallized from ethanol to aiford 4-pregnen-l7a-ol-20-one as White prisms.

For use in the identical procedure, the -16B-bromo-4- pregnen-17oc-ol-3,20-dione 3-ethylenethioketal may be replaced by: g

l6fl-br,omo-4-pregnen-,17oc-ol-3,20-dione 3-trimethylene thioketal 16B-chloro-4-pregnen-l7u-ol-3,20-dione 3-ethylene thioketal 16fl-chloro-4-pregnen-17a-ol-3,20-dione 3-trimethylenethioketal 16[i-i0do-4-pregnen-l7a-ol-3,20-dione 3-ethylenethioketal l6,6-iodo-4-pregnen-l7a-ol-3,20-dione 3'-trimethylenethio-.

ketal Found: c, 79.98; H, 10.40.

EXAMPLE XV 6a-methyl-4-pregnen-17a-0l-20-0ne acetate A solution of the crude v6oz-methyl-4-pregnen-17oc-ol- 20-one from Example XIII in 5 ml. of glacial acetic acid is treated with 4 ml. of trifiuoroacetic anhydride and the resulting solution is maintained at 4050 C. for ten minutes and then.is poured into 200 g. of ice-water mixture. After the insoluble acetylation product has become crystalline, it is filtered oil and dissolved in methylene ch10.- r'ide.. The latter solution-is washed with aqueous potassium bicarbonate, dried with magnesium sulfate, and concentrated under reduced pressure. The residue is developed onto a column of'neutral alumina. Elution with 1:1 ether-benzene affords crystalline residues of 6a-methyl-4-pregnen-l7a-ol-20-one acetate which are combined and recrystallized from methanol to afiord white prisms which melt at 168-170 C. and which have an infrared spectrum identical with that of material prepared by an earlier, alternative method.

M Max.: 5.75, 5.82, 7308.00, 1037 It is to be understood that the invention is not to be limited to the exact details of operation or the exact compounds shown and described as obviousv modifications and equivalents will be apparent to one skilled in the art,

and the .invention'is therefore to be limited only by the scope of the appended claims.

Whatisclaimed is:

S. 1. A compound of the formula selected from the group consisting of (I) (on i wherein R is selected from the group consisting of hydrogen and methyl, and n is an integer-from 2 to 3, and (II) to on (lo Vlfi S l wherein 50 L... OH m wherein R is selected from the group consisting of hydrogen and methyl,

R is selected from the group consisting of bromine,

chlorine and iodine, and

n is an integer from 2 to 3.

12. 6a-methyl-16 8-bromo 4 pregnen 172-01-320- dione 3-ethylenethioketal.

13. 6u-methyl-16B-br0mo 4 pregnen-17a-ol-3,20- 35 18. A method of preparing a compound of the formula wherein R is selected from the group consisting of hydrogen and methyl, and n is an integer from 2 to 3, which comprises reacting a compound of the formula wherein R has the meaning set forth above with an alkyl dithiol selected from the group consisting of ethanedithiol, 1,2-propane dithiol and 1,3-propanedithiol, in the presence of pyridine hydrochloride.

References Cited by the Examiner UNITED STATES PATENTS 2,744,108 5/56 Ralls 260--239.5 2,773,868 12/56 Agnello et a1 260239.55 2,789,989 4/57 Julian et al. 260239.55 2,887,478 5/59 Julian et a1. 260-2395 LEWIS GOTTS, Primary Examiner. 

1. A COMPOUND OF THE FORMULA SELECTED FROM THE GROUP CONSISTING OF (I) 